Fludarabine phosphate, a synthetic purine nucleoside, is an antineoplastic agent. Fludarabine phosphate differs from the physiologic nucleosides, adenosine and deoxyadenosine, in that the sugar moiety is arabinose instead of ribose or deoxyribose, respectively, and by the addition of a fluorine atom to the purine base adenine. The drug is a purine antagonist antimetabolite. Fludarabine also is structurally related to vidarabine (9-β-D-arabinofuranosyladenine, ara-A), differing only by the presence of a fluorine atom at position 2 of the purine moiety and a phosphate group at position 5 of the arabinose moiety.
Fludarabine (2-fluoro-ara-A) is commercially available as the phosphate salt (2-fluoro-ara-AMP), the structure of which may be represented as shown below:

Commercially available fludarabine phosphate powder for injection is a white, lyophilized solid cake containing fludarabine (50 mg/vial) and mannitol (50 mg/vial). Following reconstitution of the drug with sterile water for injection to a concentration of 25 mg/mL, the solution has a pH of approximately 7.7. (range 7.2–8.2). After reconstitution, the product usually is combined with 100 ml or 125 ml of a pharmaceutically acceptable intravenous solution, such as aqueous 0.9% sodium chloride or 5% dextrose.
It is desirable to provide a ready-to-use stable aqueous fludarabine phosphate composition that could be administered without the need for reconstituting lyophilized fludarabine phosphate currently available. However, an impediment to the preparation of an aqueous fludarabine phosphate composition is that such compositions may not be adequately stable at ambient temperatures. Generally, ready-to-use solutions are stored and transported at refrigerated temperatures (e.g., 2° C.–8° C.) to circumvent the lower stability of ready-to-use solutions in comparison to lyophilized compositions. Still, accidental exposure of a ready-to-use compositions to elevated temperatures (i.e., temperatures at or above ambient temperature) during storage or transportation can result in unacceptable levels of degradation.
An object of the present invention is to provide a ready-to-use aqueous fludarabine phosphate composition with enhanced stability at elevated temperatures such that accidental exposure of the composition to elevated temperatures for a brief time would be less likely to result in unacceptable levels of degradation of the fludarabine phosphate.